In humans, both aging diseases such as cardiac dysfunction are associated with the formation of large deletion mutations in the mitochondrial genome (mtDNA). Despite the prominent role of large mtDNA deletions in human aging and disease, the exact molecular mechanism of mtDNA deletion formation remains unknown. I propose to use the model nematode, Caenorhabditis elegans, as a system to genetically screen for genes that are associated with the formation or accumulation of large mtDNA deletion mutations. The identification of the gene(s) responsible for preventing the formation or accumulation of mtDNA deletions would open up fundamentally new scientific avenues for dissecting the genetic pathways associated with mtDNA deletion formation. Genes identified by this study can be considered as new gene targets for human disease for both diagnosis and treatment.